What links congenital CMV, Aicardi-Goutiere's Syndrome and Non Megalencephalic Cystic Leukoencephalopathy?

A 3 year old boy came in with the history of neuroregression for the past 6 months. His head size was normal.

His MRI brain was striking. He had cysts in bilateral temporal lobes and multifocal sub cortical white matter changes in frontal and parietal-occipital lobes. 

It decided to relook at all the important leukodystrophies with cysts.

1. Megalencephalic Leukoencephalopathy with subcortical cysts- This has diffuse, extensive white matter changes. The white matter looks positively swollen. The child is usually developing normally and may develop brief deterioration after minor head trauma. In short the MRI brain looks much worse than the child. It's extremely common among the Agarwal community in India. Most importantly they all have a large head which my patient lacked.

2. Congenital CMV disease- Congenital CMV disease also presents with white matter changes and temporal cysts. They often have cortical malformations like polymicrogyria, ventriculomegaly, calcifications and cerebellar atrophy. They are symptomatic since early infancy and have microcephaly.

3. Aicardi Gautiere syndrome- They mimic congenital CMV. They present after a few weeks of life with irritability and sterile pyrexia and chillbalians. The basal ganglia calcifications are striking besides the temporal cysts and white matter changes. 

4. Cystic Leukoencephalopathy without megalencephaly- These children are symptomatic from birth with global developmental delay and very slow to static clinical progression of disease. The head size is normal and MRI brain shows temporal cysts and scattered multifocal subcortical white matte changes, which our patient had.

Congenital CMV, AGS and cystic Leukoencephalopathy without megalencephaly are called interferronopathies.

Normally viral nucleic acids trigger release of interferon. Interferon production can also be upregulated by the presence of excessive nucleic acid residues derived from what are called retro elements. These are remnants of ancient viruses in our DNA which are usually metabolised by various enzymes coded by genes like TREX1, RNAase H2 etc. Mutations in these genes result in excessive nucleic acid residues which activate interferon and cause this group of auto inflammatory disorders like Aicardi Gautieres and cystic Leukoencephalopathy without megalencephaly.  https://doi.org/10.1111/dmcn.14268

This is the key to the uncanny similarity between congenital CMV and AGS.